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JNK Inhibition by SP600125 Attenuates trans-10, cis-12 Conjugated Linoleic Acid-Mediated Regulation of Inflammatory and Lipogenic Gene Expression

  • Original Article
  • Published:
Lipids

Abstract

Supplementation with a mixture of trans-10, cis-12 (t10,c12) and cis-9, trans-11 (c9,t11) isomers of conjugated linoleic acid (CLA), or t10,c12 CLA alone, reduces body weight and fat deposition in animals and some humans. However, these anti-obesity actions of t10,c12 CLA are routinely accompanied by increased markers of inflammation and insulin resistance. Thus, we examined the extent to which blocking c-Jun NH2-terminal kinase (JNK) signaling using the JNK inhibitor SP600125 attenuated markers of inflammation and insulin resistance in primary human adipocytes treated with t10,c12 CLA. SP600125 attenuated t10,c12 CLA-mediated phosphorylation of cJun and increased protein levels of activating transcription factor (ATF) 3, two downstream targets of JNK. SP600125 attenuated t10,c12 CLA-mediated induction of inflammatory genes, including interleukin (IL)-6, IL-8, IL-1β, ATF3, monocyte chemoattractant protein (MCP)-1, and cyclooxygenase-2. Consistent with these data, SP600125 prevented t10,c12 CLA-mediated secretion of IL-8, IL-6, and MCP-1. SP600125 prevented t10,c12 CLA suppression of lipogenic genes including peroxisome proliferator activated receptor gamma, liver X receptor, sterol regulatory element binding protein, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. Additionally, SP600125 blocked t10,c12 CLA-mediated induction of suppressor of cytokine synthesis-3 and suppression of adiponectin and insulin-dependent glucose transporter 4 mRNA levels. Collectively, these data suggest that JNK signaling plays an important role in t10,c12 CLA-mediated regulation of inflammatory and lipogenic gene expression in primary cultures of human adipocytes.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AP-1:

Activator protein

apm-1:

Adiponectin

ATF:

Activating transcription factor 3

BMI:

Body mass index

BSA:

Bovine serum albumin

c9,t11 CLA:

Cis-9, trans-11 conjugated linoleic acid

t10,c12 CLA:

Trans-10, cis-12 conjugated linoleic acid

COX:

Cyclooxygenase

DEX:

Dexamethasone

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

FA:

Fatty acid

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GLUT4:

Insulin-dependent glucose transporter 4

HBSS:

Hanks balanced salt solution

IBMX:

1-methyl-3-isobutylxanthine

IL:

Interleukin

IRS:

Insulin receptor substrate

ISR:

Integrated stress response

JNK:

c-Jun-NH2-terminal kinase

LXR:

Liver X receptor

MAPK:

Mitogen-activated protein kinase

MCP:

Monocyte chemoattractant protein

MEK:

Mitogen-activated protein kinase kinase

NFκB:

Nuclear factor kappa B

PPAR:

Peroxisome proliferator activated receptor

SCD:

Stearoyl-CoA desaturase

SOCS:

Suppressor of cytokine synthesis

SREBP:

Sterol regulatory element binding protein

SV:

Stromal vascular

TG:

Triglyceride

TZD:

Thiazolidinedione

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Acknowledgments

This work was supported by grants from the National Institute of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases/Office of Dietary Supplements (NIDDK/ODS) (5R01-DK063070) to MM, the North Carolina Agriculture Research Service (NCARS 06520) to MM, the NIH 5F31DK076208 and United Negro College Fund (UNCF)-Merck fellowships to AK, and NIH F31DK084812 to KM.

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Authors and Affiliations

  1. Department of Nutrition, University of North Carolina, 318 Stone Building, PO Box 26170, Greensboro, NC, 27402-6170, USA

    Kristina Martinez & Michael K. McIntosh

  2. Department of Molecular Physiology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Arion Kennedy

Authors
  1. Kristina Martinez
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  2. Arion Kennedy
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  3. Michael K. McIntosh
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Correspondence to Michael K. McIntosh.

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Martinez, K., Kennedy, A. & McIntosh, M.K. JNK Inhibition by SP600125 Attenuates trans-10, cis-12 Conjugated Linoleic Acid-Mediated Regulation of Inflammatory and Lipogenic Gene Expression. Lipids 46, 885–892 (2011). https://doi.org/10.1007/s11745-011-3587-4

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  • DOI: https://doi.org/10.1007/s11745-011-3587-4

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